The purpose of this proposal is to conduct clinical trials of modulation of resistance to cytotoxic drugs. Studies of new modulators of MDR1/P-glycoprotein (P-gp) multidrug resistance (MDR) will continue. Additional areas of focus include: (1) modulation of other MDR mechanisms (the MDR-associated protein MRP, and the bcl-2 family of inhibitors of apoptosis); and (2) the use of P-gp inhibitors to enhance the oral bioavailability of taxanes and other P-gp substrate drugs.
Aim 1 : To conduct Phase I trials of modulation of multidrug resistance mechanisms. We will conduct 1-2 Phase I trials per year, defining toxicities, optimal doses and schedules, and drug disposition. Planned studies include: PSC 833 (PSC)/Doxil/paclitaxel; LY335979/mitoxantrone; LY335979/doxorubicin/paclitaxel; and other, new MDR1 modulators. Similar approaches will be applied to a new inhibitor of MRP, with doxorubicin and with etoposide; and antisense oligonucleotide drugs against bcl-2 and bcl-xl. We will choose these new agents based on animal toxicology, other preclinical data, and availability for clinical trials. An eventual goal is combined blockade of two mechanisms (e.g., MDR1 and MRP).
Aim 2 : To study pharmacokinetic interactions associated with modulation of drug resistance. An important issue with modulators of drug resistance is the effect of these drugs on normal tissue function and in particular on the disposition of cytotoxins. Pharmacokinetic studies will involve compartmental methods to further define drug interactions, and validation of optimal sampling strategies with Bayesian estimations. The effect of different modulators (PSC vs. LY335979) on the erythromycin breath test in patients will be used to dissect the role of cytochrome P450 3A4 in these interactions. Ancillary pharmacokinetic studies of mitoxantrone and etoposide for the ECOG and POG trials of MDR1 modulation in acute myeloid leukemias will also be supported.
Aim 3 : To enhance the oral bioavailability of MDR1-related drugs by co-administration with inhibitors of P-gp. Intestinal P-gp is a major barrier to the absorption of taxanes and other MDR1 related cytotoxins. We will co-administer modulators and cytotoxins in trials designed to enhance bioavailability, and potentially to increase the safety and convenience of chemotherapy. Patients will receive an initial course of the cytotoxin intravenously, followed by sequential courses of the cytotoxin orally together with increasing doses of the P-gp inhibitor. The first protocol in this aim will involve paclitaxel with PSC. Other cytotoxins of interest for this approach include taxotere, etoposide, and vinorelbine.
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